The purpose of the proposed project is to continue to identify and establish the pharmacological profile of agents with potential protective effects against multiple "triggers" for relapse and selectivity for cocaine-seeking behavior without producing general suppressant effects on motivated behavior. Data generated during the previous funding period have identified the mGlu[2/3] agonist LY379268, the mGlu5 antagonist MTEP, the orexin/hypocretin (Orx/Hcrt) Hcrt-1 antagonist SB334867, and the 01 receptor antagonist BD1047 as candidates meeting one or more of these criteria. The present extension of this project represents an essential next step for defining the potential of these receptors as treatment targets, and to begin to provide understanding of the neurobiological basis for the "therapeutic" effects of agents acting at these receptors. The research plan is to first establish the profile of action for LY379268, MTEP, SB334867, and BD1047 on cocaine-seeking in animal models of cue- and stress-induced relapse under clinically relevant" conditions, including (a) examination of the efficacy of these agents for reversingcue-and stress-induced reinstatement with repeated treatment and (b) examination of the effects and shifts in the dose-response profiles of these agents for reversing cue-and stress-induced reinstatement in rats with a history of escalated cocaine self-administration. These studies will be followed by examination of the potential of these agents to reverse "negative affect" associated with cocaine withdrawal, a condition that next to cue-induced craving and stress has been implicated as a critical risk factor for relapse. These studies will be conducted in rats with a history of escalated cocaine self-administration, using the defensive burying animal model of anxiety. A final objective is to establish the neurocircuitry basis for the behavioral effects of these agents using inducible transcription factor (i.e., Fos, Zif-268, Arc)neural mapping. It is expected that these studies will advance understanding of novel, potentially highly promising treatment targets for relapse prevention;and of the neuroscience of cocaine-seeking behavior and addiction, in general.